Circulation Research. 2003
Published online before print February 6, 2003, doi: 10.1161/01.RES.0000060700.55247.7C
Published online before print February 6, 2003, doi: 10.1161/01.RES.0000060700.55247.7C
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Submitted on June 19, 2002
Revised on January 29, 2003
Accepted on January 29, 2003
Peroxisome Proliferator-Activated Receptor (PPAR) 
and PPAR
/
, but not PPAR
, Modulate the Expression of Genes Involved in Cardiac Lipid Metabolism
Andries J. Gilde ;
From the Department of Physiology (A.J.G., K.A.J.v.d.L., P.H.M.W., G.J.v.d.V., M.v.B.), Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands; U 545 INSERM, Département d'Athérosclerose (G.C.), Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille, France; and Department of Pediatrics (F.R.v.d.L.), Beatrix Children's Hospital, University of Groningen, the Netherlands.
* To whom correspondence should be addressed. E-mail: Marc.vanBilsen{at}FYS.Unimaas.NL.
Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPAR
in FA-mediated expression has been demonstrated, the role of the PPAR
/
and PPAR
isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPAR (Wy-14,643), PPAR/ (L-165041, GW501516), or PPAR (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPAR and PPAR/ ligands, but not to PPAR ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPAR and PPAR/, but not by PPAR ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPAR/, the FA-induced expression of genes was mimicked by the PPAR/ ligand only, indicating that FA also act as ligands for the PPAR/ isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPAR ligands. However, addition of PPAR and PPAR/ ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPAR, PPAR/, but not PPAR, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPAR/ in cardiac disease.
Key words: cardiomyocytes • H9c2 cells • fatty acids • gene expression • uncoupling protein
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